The field of the invention is Alzheimer's disease.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system involving loss of memory and cognitive function. Neuropathological hallmarks of AD extracellular amyloid plaques, whose major component is the A.beta. peptide, a proteolytic product of the .beta.-amyloid precursor protein (APP).
Dominant mutations in any of three mammalian genes, PS1, PS2, and APP are causative for the early-onset, familial form of AD (FAD). PS1 and PS2 encode related proteins-, while APP encodes the amyloid precursor protein (APP) (reviewed in Hardy, Trends Neurosci. 20:154-159, 1997), from which the A.beta. peptide is generated by proteolytic processing.
Since presenilin-1 (PS1) and presenilin-2 (PS2) were first identified as genes mutated in FAD, much effort has been devoted to elucidating the biological function of presenilins in normal and disease states. Two lines of evidence support a hypothesis that presenilins affect proteolytic processing of APP First, PS(FAD) mutations are associated with an increase in a longer, more amyloidogenic form of A.beta. known as A.beta.42 ; and second, levels of A.beta. are decreased several-fold in neurons derived from PS1 knockout mice relative to PS1(+) control mice. Moreover, in neurons, A.beta. 42 may be generated in the endoplasmic reticulum, where presenilins have been localized.
C. elegans has three presenilin genes, spe-4 (spermatogenesis defective) (L'Hernault, et al., J. Cell Biol., 119:55-68, 1992), sel-12 (suppressor and/or enhancer of lin-12) (Levitan et al., Nature 377:351-354, 1995), and hop-1 (homolog of presenilin) (Li et al., Proc. Natl. Acad. Sci USA 94:12204-12209, 1997). Rescue experiments using transgenes have shown that human PS1 and PS2 can substitute for SEL-12, demonstrating that presenilin function has been conserved from nematodes to mammals.
Construction of a nematode having mutations in nematode presenilin genes and also having phenotypes useful for screens for genes associated with the biological pathway and for screens for compounds affecting the biological pathway in which these genes function would be useful for identifying therapeutics and causative agents involved in AD.